Nongenomic Actions Of Aldosterone Research Articles

Enhanced Thrombotic Responses Are Associated With Striatin Deficiency and Aldosterone.

BackgroundIn addition to its role on blood pressure, aldosterone (ALDO) also affects the hemostatic system leading to increased experimental thrombosis. Striatin is an intermediate in the rapid, nongenomic actions of ALDO. Striatin heterozygote knockout (Strn +/‐ ) mice have salt sensitivity of blood pressure and mildly chronically increased ALDO levels. In addition, in humans, striatin polymorphic gene variants are associated with increased salt sensitivity of blood pressure. Thus, we hypothesized that striatin deficiency would be associated with an increased prothrombotic response.Methods and Results Strn+/ ‐ mice and wild‐type littermates were maintained on a liberal sodium diet (1.6%). We measured in vivo thrombus formation following laser‐induced injury in cremaster arterioles using intravital microscopy. Mice were randomized to intravenous administration of ALDO or its vehicle. Acutely, ALDO increased thrombotic responses in wild‐type mice (P<0.01) versus controls within minutes as determined by increased platelet accumulation and fibrin deposition at the site of laser injury. We then compared thrombus formation without ALDO administration in Strn+/‐ and wild‐type mice. Strn+/‐ mice showed highly significant increases in laser‐induced thrombosis (P<0.001), as shown by increased platelet accumulation and fibrin deposition. Interestingly, the response in the Strn+/‐ mice basally was far greater than the wild‐type mice with ALDO administration, and ALDO administration produced no additional effect on thrombus responses in Strn+/‐ mice.ConclusionsThese results demonstrate a novel protective role of striatin in experimental thrombosis. Such a protective effect may be reduced in human striatin risk allele carriers, given the similar salt sensitivity of blood pressure in these individuals and Strn+/‐ mice.

Non-Genomic Effects of Aldosterone.

Encouraging changes in the steroid hormone receptor field from initially questioning the role of non-genomic actions of steroid hormones to acceptance of the concept that the acute, membrane-centric actions are linked and/or regulate the nuclear actions. The focus of this chapter is how the non-genomic effects are linked to the longer lasting, genomic actions of aldosterone. By non-genomic we refer to the rapid actions that occur within minutes do not require transcription or translation and occur in both classical MR target organs (kidney and colon) and non-epithelial tissues (blood vessels, heart, and adipose). The mechanism of rapid non-genomic actions of aldosterone varies between tissues. As a result, this chapter is viewed through the lens of how the non-genomic and genomic actions of aldosterone are linked in cardiovascular disease. Specifically, regulation of sodium flux in the myocardium has an important role in pathogenesis of cardiac arrhythmia. Since there are now recognized gender differences in cardiovascular disease, we also include preliminary studies to investigate the interaction of sex steroid hormones with the ligand binding pocket of the mineralocorticoid receptor. Overall, we aim to showcase how the non-genomic effects of aldosterone potentially modulate the genomic effects and represent additional targets for intervention.

Nongenomic action of aldosterone on colocalization of angiotensin II type 1 and type 2 receptors in rat kidney

Previous in vitro studies have demonstrated that angiotensin II type 1 and type 2 receptors (AT1R and AT2R) are co-localized and can form AT1R/AT2R dimerization in rat proximal tubular cells. Aldosterone non-genomically enhances angiotensin II receptor dimerization. We found no other in vivo studies in the literature regarding the effect of aldosterone on colocalization of AT1R and AT2R in whole kidney. Male Wistar rats were intraperitoneally injected with either normal saline solution (sham group) or aldosterone (experimental group). Colocalization of renal AT1R and AT2R proteins was examined by double immunohistochemical staining. The colocalization of AT1R and AT2R proteins was more prominent in the glomerulus, distal convoluted tubules, and cortical collecting ducts while colocalization was weak and diffused in the proximal convoluted tubules and peritubular capillaries in both groups. Our in vivo study showed aldosterone did not alter a constitutive colocalization of AT1R and AT2R proteins in the renal cortex and medulla. However, these proteins were colocalized more prominently in the renal cortex.

Aldosterone signaling through transient receptor potential melastatin 7 cation channel (TRPM7) and its α-kinase domain

We demonstrated a role for the Mg2+ transporter TRPM7, a bifunctional protein with channel and α-kinase domains, in aldosterone signaling. Molecular mechanisms underlying this are elusive. Here we investigated the function of TRPM7 and its α-kinase domain on Mg2+ and pro-inflammatory signaling by aldosterone. Kidney cells (HEK-293) expressing wild-type human TRPM7 (WThTRPM7) or constructs in which the α-kinase domain was deleted (ΔKinase) or rendered inactive with a point mutation in the ATP binding site of the α-kinase domain (K1648R) were studied. Aldosterone rapidly increased [Mg2+]i and stimulated NADPH oxidase-derived generation of reactive oxygen species (ROS) in WT hTRPM7 and TRPM7 kinase dead mutant cells. Translocation of annexin-1 and calpain-II and spectrin cleavage (calpain target) were increased by aldosterone in WT hTRPM7 cells but not in α-kinase-deficient cells. Aldosterone stimulated phosphorylation of MAP kinases and increased expression of pro-inflammatory mediators ICAM-1, Cox-2 and PAI-1 in Δkinase and K1648R cells, effects that were inhibited by eplerenone (mineralocorticoid receptor (MR) blocker). 2-APB, a TRPM7 channel inhibitor, abrogated aldosterone-induced Mg2+ responses in WT hTRPM7 and mutant cells. In 2-APB-treated ΔKinase and K1648R cells, aldosterone-stimulated inflammatory responses were unchanged. These data indicate that aldosterone stimulates Mg2+ influx and ROS production in a TRPM7-sensitive, kinase-insensitive manner, whereas activation of annexin-1 requires the TRPM7 kinase domain. Moreover TRPM7 α-kinase modulates inflammatory signaling by aldosterone in a TRPM7 channel/Mg2+-independent manner. Our findings identify novel mechanisms for non-genomic actions of aldosterone involving differential signaling through MR-activated TRPM7 channel and α-kinase.

Evolving research in nongenomic actions of aldosterone

Aldosterone is now recognized as an increasingly important contributor to cardiometabolic pathology via inflammatory and fibrosis-related pathways in addition to its classically described role in sodium and volume regulation. Consequently, much effort has been directed towards characterizing the molecular pathways involved in aldosterone-mediated fibrosis and inflammation. What was once viewed as straightforward steroid hormone biology is now appreciated as a highly complex and tightly regulated series of pathways and interactions. These recognitions have fuelled a multidisciplinary effort to identify precisely how aldosterone mediates intracellular activation of both genomic (latent) and nongenomic (rapid) mechanisms of influence. This review will explore recent novel pathways regulating aldosterone action, focusing on the nongenomic pathways. Several recent discoveries have redefined our understanding of aldosterone interactions at the cellular level. This includes activation of the mineralocorticoid receptor at the plasma membrane instead of via classical nuclear hormone receptor interaction, and identification of novel cofactor scaffolding proteins that modify aldosterone influence at the cellular level. In addition, aldosterone activation of secondary messenger system cascades can occur directly and independent of mineralocorticoid receptor interaction. Substantial progress in detailing the molecular biology of aldosterone regulation and action should facilitate study of how it exerts detrimental effects in cardiometabolic diseases. However, to date, the clinical impact of these discoveries has not been validated. Translational efforts are now required to determine if novel therapeutic targets can be developed.

New evidence for vascular interactions between aldosterone, angiotensin II and antioxidants in isolated smooth muscle cells of rats

Abstract Accumulating evidence suggests that the nongenomic cardiovascular actions of aldosterone are produced by varied cellular pathways and mediated by a multitude of messenger systems including the reactive oxygen and nitrogen species. Considering the involvement of the oxidative and nitrosative stress in the pathways leading to the activation of the angiotensin — aldosterone system, in the current study we tried to evaluate the functional interactions between aldosterone, angiotensin II and antioxidants in isolated vascular smooth muscle of aortic rings from rats. Our data provide additional arguments that the nongenomic actions of aldosterone on aortic smooth muscle cells of rats are a question of cross-talk and balance between its rapid vasoconstrictor and vasodilator effects, as result of the activation of reactive oxygen species in the first case and of nitrogen species in the second. In this way, it seems that at low ambient oxidative stress, aldosterone promotes nitric oxide (NO) production and vasodilatation, while in situations with increased oxidative stress the endothelial dysfunction and detrimental effects induced by vasoconstriction will prevail. Thus, aldosterone could be considered both “friend and foe”. This could be relevant for the ways in which aldosterone damages cardiovascular functions and could lead to significant therapeutic improvements.

Antiapolipoprotein A-1 IgG Chronotropic Effects Require Nongenomic Action of Aldosterone on L-Type Calcium Channels

Autoantibodies to apolipoprotein A-1 (antiapoA-1 IgG) have been shown to be associated with higher resting heart rate and morbidity in myocardial infarction patients and to behave as a chronotropic agent in the presence of aldosterone on isolated neonatal rat ventricular cardiomyocytes (NRVC). We aimed at identifying the pathways accounting for this aldosterone-dependent antiapoA-1 IgG-positive chronotropic effect on NRVC. The rate of regular spontaneous contractions was determined on NRVC in the presence of different steroid hormones and antagonists. AntiapoA-1 IgG chronotropic response was maximal within 20 min and observed only in aldosterone-pretreated cells but not in those exposed to other steroids. The positive antiapoA-1 IgG chronotropic effect was already significant after 5 min aldosterone preincubation, was dependent on 3-kinase and protein kinase A activities, was not inhibited by actinomycin D, and was fully abrogated by eplerenone (but not by spironolactone), demonstrating the dependence on a nongenomic action of aldosterone elicited through the mineralocorticoid receptor (MR). Under oxidative conditions (but not under normal redox state), corticosterone mimicked the permissive action of aldosterone on the antiapoA-1 IgG chronotropic response. Pharmacological and patch-clamp studies identified L-type calcium channels as crucial effectors of antiapoA-1 IgG chronotropic action, involving two converging pathways that increase the channel activity. The first one involves the rapid, nongenomic activation of the phosphatidylinositol 3-kinase enzyme by MR, and the second one requires a constitutive basal protein kinase A activity. In conclusion, our results indicate that, on NRVC, the aldosterone-dependent chronotropic effects of antiapoA-1 IgG involve the nongenomic activation of L-type calcium channels.

Aldosterone stimulates vacuolar H+-ATPase activity in renal acid-secretory intercalated cells mainly via a protein kinase C-dependent pathway

Urinary acidification in the collecting duct is mediated by the activity of H(+)-ATPases and is stimulated by various factors including angiotensin II and aldosterone. Classically, aldosterone effects are mediated via the mineralocorticoid receptor. Recently, we demonstrated a nongenomic stimulatory effect of aldosterone on H(+)-ATPase activity in acid-secretory intercalated cells of isolated mouse outer medullary collecting ducts (OMCD). Here we investigated the intracellular signaling cascade mediating this stimulatory effect. Aldosterone stimulated H(+)-ATPase activity in isolated mouse and human OMCDs. This effect was blocked by suramin, a general G protein inhibitor, and GP-2A, a specific G(αq) inhibitor, whereas pertussis toxin was without effect. Inhibition of phospholipase C with U-73122, chelation of intracellular Ca(2+) with BAPTA, and blockade of protein kinase C prevented the stimulation of H(+)-ATPases. Stimulation of PKC by DOG mimicked the effect of aldosterone on H(+)-ATPase activity. Similarly, aldosterone and DOG induced a rapid translocation of H(+)-ATPases to the luminal side of OMCD cells in vivo. In addition, PD098059, an inhibitor of ERK1/2 activation, blocked the aldosterone and DOG effects. Inhibition of PKA with H89 or KT2750 prevented and incubation with 8-bromoadenosine-cAMP mildly increased H(+)-ATPase activity. Thus, the nongenomic modulation of H(+)-ATPase activity in OMCD-intercalated cells by aldosterone involves several intracellular pathways and may be mediated by a G(αq) protein-coupled receptor and PKC. PKA and cAMP appear to have a modulatory effect. The rapid nongenomic action of aldosterone may participate in the regulation of H(+)-ATPase activity and contribute to final urinary acidification.

Acute mineralocorticoid receptor blockade produces rapid renal vasodilation with no impairment of autoregulation in vivo

Chronic blockade of the mineralocorticoid receptor (MR) significantly attenuates obesity‐induced rise in mean arterial pressure (MAP), sodium reabsorption and glomerular filtration rate (GFR). The mechanisms and immediate time‐course underlying these responses are not known but may involve rapid, non‐genomic actions of aldosterone at the MR. We determined the immediate renal hemodynamic response to MR blockade in anesthetized Sprague‐Dawley rats instrumented for measurement of MAP and renal blood flow (RBF). Animals were infused with the MR antagonist potassium canrenoate (20mg/kg i.v) or saline. Within 1 min of MR blockade, MAP fell (−9.1±3.6 mmHg, n=5, p&lt;0.001) which was absent in saline controls (−0.4±1.6 mmHg, n=4). RBF rose (0.3±0.1 mL/min, n=5, p&lt;0.001) with no change with saline alone (−0.1±0.1 mL/min, n=4). Renal arterial conductance (RBF/MAP) rose only with MR blockade (0.01±0.003 mLmin−1 · mmHg−1, n=5, p&lt;0.001; saline −0.0003±0.001 mLmin−1 · mmHg−1, n=4) reflecting renal vasodilatation. Autoregulatory index was comparable in both groups (canrenoate 0.34±0.2 vs saline 0.21±0.1). We demonstrate rapid renal vasodilation in response to MR blockade in vivo suggesting differences between acute and chronic modulation of renal hemodynamics by aldosterone. NIH HL51972, CIHR

Expanding view of aldosterone action, with an emphasis on rapid action

1. The actions of aldosterone beyond the 'mineralocorticoid' designation continue to attract intense interest. In recent years, two aspects have received particular attention. These are, first, the potentially damaging direct actions of aldosterone on the heart and vascular system, and the clear benefit, as illustrated by the Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival trials, of including antialdosterone therapy in the treatment of cardiovascular disease. 2. Second, the importance of non-genomic actions of aldosterone has become clear, some of which might possibly be mediated by distinct membrane receptors. Over the past 5 years, evidence has arisen to bring these two aspects together, and now emphasizes the role of rapid, nongenomic actions of aldosterone on cardiovascular events. 3. However, despite many years of study, there is still no clear view of the nature of the receptors mediating non-genomic responses. We examine the evidence, and suggest that in many cases non-genomic actions are attributable to classical mineralocorticoid receptors.

Nongenomic steroid actions: completing the puzzle. Aldosterone as an example.

In the common unidimensional theory of steroid action, steroids bind to intracellular receptors and modulate nuclear transcription and thus protein synthesis. These genomic steroid effects, being characterized by their delayed onset of action and their dependence on transcription and protein synthesis, have been known for several decades. In contrast, very rapid actions of steroids, which are considered to be of nongenomic origin, have been recognized more widely and characterized in detail only during the past ten years. Specific rapid effects of steroids and related hormones like vitamin D3 and thyroid hormones on cellular function involve a conventional second messenger cascade which in most cases includes phospholipase C, phosphoinositide turnover, intracellular pH and intracellular calcium ([Ca2+]i), and protein kinase C. Furthermore, binding sites in membranes have been characterized exposing binding features compatible with an involvement in rapid-steroid signaling. Characteristics of putative membrane receptors are completely different from those of classic intracellular steroid receptors; this also includes the inability of classic steroid receptor antagonists to inhibit those rapid nongenomic steroid actions. The physiological and pathophysiological relevance of these effects is still largely unclear, but their existence has been proven recently even under in vivo conditions. New drugs modulating nongenomic steroid actions may find applications in various areas such as the cardiovascular and central nervous systems, infertility and electrolyte homeostasis. This short review focuses mainly on the nongenomic actions of aldosterone and their cardiovascular implications.

Nongenomic Actions of Aldosterone on the Renal Tubule

Aldosterone plays a major role in the maintenance of sodium, potassium, and acid-base balance through its effects on renal electrolyte excretion. This regulation is achieved through aldosterone-induced stimulation of Na+ absorption, K+ secretion, and H+ secretion by the distal nephron, particularly segments of the collecting duct.1–3 These classical actions are mediated through binding of aldosterone to the intracellular mineralocorticoid receptor (MR). The hormone-receptor complex translocates to the nucleus, where it promotes gene transcription and the production of proteins that modulate the expression and activity of the epithelial Na+ channel (ENaC) and other ion transport proteins.1,4–6 Regulatory actions of aldosterone via the MR play an important role in the normal maintenance of blood pressure but also have been implicated in the pathogenesis of hypertension and the progression of renal disease.6–9 In addition to their classical actions, aldosterone and other steroid hormones influence cell processes through nongenomic mechanisms.10,11 Nongenomic effects of aldosterone have been demonstrated in many different epithelial and nonepithelial tissues and are defined by (1) an insensitivity to inhibitors of transcription (actinomycin D) and translation (cycloheximide) and (2) a rapid time course (seconds to a few minutes) that is incompatible with gene regulation and de novo protein synthesis. A rapid onset of action is a sufficient but not necessary criterion for a nongenomic effect. Some nongenomic effects can occur with a slower time course. An additional feature often associated with nongenomic effects is that they are not blocked by spironolactone and/or other MR antagonists, consistent with mediation via a nonclassical aldosterone receptor.10,11 Although compelling evidence exists for rapid effects of aldosterone unrelated to the MR, a novel aldosterone receptor for nongenomic regulation has not been identified, and there is evidence that nongenomic actions of aldosterone can be mediated via the classical …

Can the dextroenantiomer of the aromatase inhibitor fadrozole be useful for clinical investigation of aldosterone-synthase inhibition?

The beneficial effects of spironolactone, eplerenone, amiloride and potassium in preventing cardiovascular damage in various experimental models of salt-induced hypertension can be dissociated from blood pressure effects, and have drawn attention to the direct genomic and non-genomic actions of aldosterone at the level of the vessels, the heart and the kidneys. Exposure to endogenous aldosterone could be decreased by direct and specific aldosterone-synthase inhibition. FAD 286A, the dextroenantiomer of the aromatase inhibitor fadrozole, might be a first candidate to investigate in humans, the physiological impact and therapeutic properties of aldosterone-synthase inhibition, especially in various forms of primary aldosteronism.

Hypertension and the expanding role of aldosterone

Aldosterone is the principal human mineralocorticoid and plays a significant role in hypertension and cardiovascular morbidity. Classically, aldosterone is synthesized in the adrenal zona glomerulosa and binds to mineralocorticoid receptors in the cytosol of target epithelial cells. Nonepithelial and rapid nongenomic actions of aldosterone have now also been described, as well as a number of extra-adrenal sites of synthesis, including the central nervous system. Recent studies also suggest that elevated aldosterone biosynthesis, as defined by an increased aldosterone-to-renin ratio, is present in up to 15% of essential hypertensives and that aldosterone levels predict the development of hypertension in normotensive individuals. Furthermore, mineralocorticoid-receptor antagonists demonstrate that aldosterone is a significant contributor to cardiovascular pathology. In this article, we present the evidence behind these findings and explore the expanding role of aldosterone as a key cardiovascular hormone.

Nongenomic Renal Effects of Aldosterone

There is increasing evidence for a dependency on aldosterone in the development of hypertension.1 How aldosterone influences the physiology that determines blood pressure or for that matter promotes the pathophysiology of high blood pressure turns out to be less than straightforward. There is the genomic pathway that begins with the binding of aldosterone to the classical mineralocorticoid receptor (MR) and ends with sodium reabsorption at the distal nephron. But aldosterone can convey nongenomic influences as well, actions that have received less attention, possibly in part because they seem counterintuitive to our genomic view of biology. Adding to the complexity of aldosterone’s actions is the fact that there are also nonepithelial (nondistal nephron) targets of aldosterone, such as the heart, the vasculature, the kidney, and other sites. In this issue of Hypertension , Schmidt et al2 describe a rapid (thus nongenomic) effect of administered aldosterone to increase resistance in renal vasculature (a nonepithelial target) in healthy human subjects. The findings follow on the heels of a rather large body of work on the genomic actions of aldosterone. Aldosterone’s nongenomic effects were first recognized more than a decade before an aldosterone-inducible gene was identified in the late 1990s.3 A nongenomic action characteristically occurs almost immediately, usually within several minutes,4 before sufficient time has elapsed for gene …

Nongenomic actions of aldosterone: Physiological or pathophysiological role?

The actions of aldosterone are usually divided into persistent genomic mediated by the classical mineralocorticoid receptor versus acute nongenomic actions. Rapid, nongenomic effects of aldosterone have been shown in a variety of tissues, although the physiological relevance of these nongenomic actions remains to be established. There is now growing evidence that both the nongenomic and genomic actions of aldosterone, are mediated via the same classical mineralocorticoid receptor, and there is cross talk between the nongenomic and classical actions of steroid hormones. Activation of tissue-specific, second messenger pathways may contribute to integration of nongenomic and classical actions of aldosterone. Further studies are required to determine the physiological or pathophysiological role of these nongenomic actions of aldosterone and whether they might amplify pathophysiological effects of aldosterone.

The new biology of aldosterone

Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific 'aldosterone-induced' proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue. There is also evidence that aldosterone can be synthesised in other tissues; the most convincing evidence relates to the central nervous system. However, suggestions that aldosterone is produced in the heart remain controversial, and adrenal derived aldosterone is the principal source of circulating and locally available hormone. Recent studies have shown major therapeutic benefits of mineralocorticoid receptor antagonism in cardiac failure, which emphasise the importance of aldosterone in causing adverse cardiovascular pathophysiological effects. Additional evidence demonstrates that aldosterone levels predict development of high blood pressure in normotensive subjects, while it is now clear that increased aldosterone action contributes to hypertension and cardiovascular damage in approximately 10% of patients with established hypertension. These new findings highlight the role of aldosterone as a key cardiovascular hormone and extend our understanding of its role in determining adverse cardiovascular outcomes.

Aldosterone Nongenomically Worsens Ischemia Via Protein Kinase C-Dependent Pathways in Hypoperfused Canine Hearts

Rapid nongenomic actions of aldosterone independent of mineralocorticoid receptors (MRs) on vascular tone are divergent. Until now, the rapid nongenomic actions of aldosterone on vascular tone of coronary artery and cardiac function in the in vivo ischemic hearts were not still fully estimated. Furthermore, although aldosterone can modulate protein kinase C (PKC) activity, there is no clear consensus whether PKC is involved in the nongenomic actions of aldosterone on the ischemic hearts. In open chest dogs, the selective infusion of aldosterone into the left anterior descending coronary artery (LAD) reduced coronary blood flow (CBF) in the nonischemic hearts in a dose-dependent manner. Also, in the ischemic state that CBF was decreased to 33% of the baseline, the intracoronary administration of aldosterone (0.1 nmol/L) rapidly decreased CBF (37.4+/-3.8 to 19.3+/-5.2 mL/100 g/min; P<0.05), along with decreases in fractional shortening (FS) (8.4+/-0.7 to 5.4+/-0.4%; P<0.05) and lactate extraction rate (LER) (-31.7+/-2.9 to -41.4+/-3.7%; P<0.05). The decrease in CBF was reproduced by the infusion of bovine serum albumin-conjugated aldosterone. Notably, these aldosterone-induced deteriorations of myocardial contractile and metabolic functions were blunted by the co-administration of GF109203X, an inhibitor of PKC, but not spironolactone. In addition, aldosterone activated vascular PKC. These results indicate that aldosterone nongenomically induces vasoconstriction via PKC-dependent pathways possibly through membrane receptors, which leads to the worsening of the cardiac contractile and metabolic functions in the ischemic hearts. Elevation of plasma or cardiac aldosterone levels may be deleterious to ischemic heart disease through its nongenomic effects.

The Nongenomic Actions of Aldosterone

Aldosterone has physiological effects to regulate fluid and electrolyte homeostasis across epithelia and proinflammatory effects on a variety of nonepithelial cells in the context of inappropriate salt status. These effects are mediated by mineralocorticoid receptors, members of a large family of nuclear transcription factors, by DNA-directed, RNA-mediated protein synthesis. Rapid effects of aldosterone, insensitive to actinomycin D or cycloheximide and thus clearly nongenomic, have been convincingly documented in a variety of epithelial and nonepithelial tissues. Despite strenuous attempts, isolation of a nonclassical membrane receptor for aldosterone has proven unsuccessful, and rapid nongenomic effects mediated by classical mineralocorticoid receptors are increasingly recognized in the kidney, heart, and vascular wall. The mechanism of rapid nongenomic actions of aldosterone may vary between tissues in terms of pathways; in addition, what remains to be established is the physiological role of aldosterone action via such rapid nongenomic mechanisms and how they might synergize with the longer time course genomic actions of mineralocorticoids.

Rapid natriuretic action of aldosterone in the rat.

Rapid, nongenomic actions of aldosterone have been demonstrated in a number of cell types in vitro, including renal cell lines, but there remains little direct evidence that it is able to exert rapid effects on the kidney in the whole animal. Accordingly, the aim of this study was to determine whether aldosterone induces rapid changes in the renal handling of electrolytes or acid-base balance in the anesthetized rat. With the use of a servo-controlled fluid replacement system, spontaneous urine output by anesthetized male Sprague-Dawley rats was replaced with 2.5% dextrose. After a 3-h equilibration and a 1-h control period, rats were infused with aldosterone (42 pmol/min) or vehicle for 1 h. Aldosterone infusion induced a rapid (within 15 min) increase in sodium excretion that peaked at 0.24 +/- 0.08 compared with 0.04 +/- 0.01 micromol x min(-1) 100 x body weight(-1) (P = 0.041) in the vehicle-infused rats. This natriuresis was not associated with changes in glomerular filtration rate; urine flow rate; potassium, chloride, or bicarbonate excretion; or urine pH. The mechanisms involved are unclear, but because we have previously shown that aldosterone stimulates a rapid (4 min) increase in cAMP generation in the rat inner medullary collecting duct (IMCD) (Sheader EA, Wargent ET, Ashton N, and Balment RJ. J Endocrinol 175: 343-347, 2002), they could involve cAMP-mediated activation of the cystic fibrosis transmembrane conductance regulator chloride channel, which drives sodium secretion in the IMCD.